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1 From the Departments of Ophthalmology and 2 Neurology, Mount Sinai School of Medicine, New York University, New York.
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Abstract |
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METHODS. An approximate doubling of IOP was induced in one eye (G) of female Wistar rats (150–180 g) by cautery of 3 episcleral/limbal veins. At intervals over 3 to 4 months, measurements of IOP and ERG changes (contact-lens electrode) were made in both the G and contralateral normal (N) eyes. At the end of 3 to 4 months of elevated IOP, RGCs were fluorescently labeled with Fluorogold (retrogradely from the superior colliculus), or retinas were labeled by intravitreal injection of a mitochondrial potential indicator dye and stained for apoptotic nuclei with a DNA dye. Flatmounts of fixed, dye-labeled retinas were examined by epifluorescence, confocal, or interference contrast microscopy.
RESULTS. Elevated IOP was consistently maintained for up to 4 months in G eyes, but ERG a- and b-waves showed a statistically significant decline, of 30% to 40% in amplitude, after 3 months. Loss of RGCs in G retinas was primarily focal with no statistically significant loss demonstrable outside of the focal areas when assessed by an area sampling method for counting RGCs, which totaled 2% to 3% of the entire retinal area. Mitochondrial membrane potential of cells in the RGC layer was reduced by 17.5% (P < 0.05) in regions surrounding areas of focal loss compared with comparable locations in control N eyes. After 3.5 months’ elevated IOP the G retinas showed cell nuclei at various stages of apoptosis, from initial DNA condensation to fragmentation.
CONCLUSIONS. The three-vein episcleral/limbal vein occlusion model for inducing
glaucomatous pathology in the rat eye gives a consistent long-term
elevation of IOP. After 3 to 4 months of 
100% increased IOP, the
ERG responses begin to decline, there is a variable focal loss of RGCs,
and some of the remaining RGCs show characteristics of stress and
apoptosis. These changes seem consistent with retinal damage in human
glaucoma (focal field defects), and this rat model appears to mimic
some features of primary open-angle glaucoma.
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Introduction |
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Several investigators have devised various ways to induce elevated IOP in the rat eye with the objective of impeding the flow of aqueous humor out of the eye. The first one, the Moore–Morrison model, involves injection of hypertonic saline into limbal aqueous humor collecting veins,1 and the Shareef–Sharma model2 uses cautery of 2 or 3 of the episcleral/extraorbital veins to block outflow of the aqueous humor. The most recent rat glaucoma model involves trabecular laser photocoagulation after injection of India ink into the anterior chamber.3
Each of the aforementioned rat glaucoma models has advantages and
disadvantages. Hypertonic saline injection has the advantage of
impeding aqueous outflow close to Schlemm’s canal. Potential
disadvantages of this model are that multiple saline injections may be
needed, the level of IOP elevation is variable for individual rats, and
optic nerve damage does not show gradation or correlate completely with
time and degree of IOP elevation.4
The laser
photocoagulation model has the advantage that the initial pathology is
localized to the trabecular meshwork. However, multiple lasering is
required to achieve 60% elevation of IOP and peripheral anterior
synechiae develop, which contribute to the IOP elevation.3
The Shareef–Sharma model has the advantage that it is technically
easier than the two models discussed above and that it gives a more
consistent long-term IOP elevation in groups of animals. The
disadvantage of this procedure is that blood flow out of the eye is
impeded by the occlusion of veins leaving the globe, which can cause
congestion in the intraocular vasculature. Thus, the elevation of IOP
may be caused in part by the vascular congestion and by partial block
of aqueous humor outflow. Although the retinal blood vessels appear
normal by funduscopic examination,5
6
it is uncertain to
what degree retinal pathology may be affected by vascular congestion
and/or decreased blood flow separate from the elevation of IOP in this
model.
In a recently published study to assess the effects of high IOP on retinal pathology in the vein–occlusion model, the RGC cells were retrogradely dye-labeled from the superior colliculus before induction of elevated IOP.7 Thus, in this prelabeling procedure the RGCs may be subjected to two concurrent insults for the duration of the experiment: presence of the intracellular dye and elevated IOP. The objective of the present investigation was to achieve and characterize a rat glaucoma model with consistently elevated IOP to facilitate evaluation of potential neuroprotective agents administered on a long-term basis. The present study differs from similar previous studies,7 8 which used the 2-vein Shareef–Sharma procedure,2 because 3-vein occlusion was used and because a high IOP was maintained for a longer time, 12 to 15 weeks. Both IOP and ERG changes were assessed at intervals over this period. A most important difference from previous studies is that the labeling of RGCs was performed only at the end of the period of elevated IOP, at which time the glaucomatous retinas were assessed for the presence of apoptotic markers (condensed nuclear DNA and loss of mitochondrial membrane potential) in cells located in the RGC layer.
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Methods |
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Induction of Elevated IOP
Fifteen female Wistar rats (180–200 g) were anesthetized with an
intramuscular injection of 0.1 to 0.15 ml of a mixture of acepromazine
maleate, xylazine, and ketamine (AXK; 1, 9, and 45 mg/ml,
respectively). The surgery was performed on one eye (G), essentially as
described by Shareef et al.,2
by severing two dorsal
episcleral veins located near the superior rectus muscle and one
temporal episcleral vein near the lateral rectus muscle with a standard
disposable ophthalmic cautery. After surgical isolation, the veins were
lifted up and away from adjacent tissues with a 3-mm-wide wooden
spatula (made from a tongue depressor) before applying the cautery.
Great care was taken to avoid thermal damage and touching the
surrounding tissues with surgical instruments. The contralateral
control eye (N eye) was sham-operated by similarly isolating the veins
but not cauterizing them. By the end of the surgery (30 minutes) the
IOP was already elevated to >30 mm Hg in the cauterized eye. The eyes
were flushed with saline, then treated with antibiotic ointment. In one
group of rats, after the conjunctival incision had healed (4–5 days),
a subconjuctival injection of 50 µl of Adrucil (Pharmacia,
Kalamazoo, MI), which is a solution of 5-fluorouracil (5-FU) 50 mg/ml,
was given under AXK anesthesia to both eyes. Injections of 5-FU were
repeated 4 to 5 more times at 3- to 4-day intervals in both eyes. In a
second group of 10 rats not treated with 5-FU the IOP was determined at
5-day intervals for 15 days after surgery, and their eyes were not
further evaluated.
Measurement of IOP
IOP was determined on both eyes using the Tono-Pen XL (Mentor,
Norwell, MA)9
immediately after surgery and then at 5-day
or 2-week intervals in AXK-anesthetized rats with 0.5% proparacaine
topical local anesthesia. The Tonopen probe was applied multiple times
to the cornea to activate the instruments’ built-in microprocessor
averaging analysis of 4 consecutive signals. Probe applications were
made until 4 to 5 averages were obtained, each with a coefficient of
variation <5%. These 4 or 5 average values from each rat were again
averaged, and the resultant mean value was used to compute the group
mean IOP ± SD.
Measurement of ERG Changes
Scotopic ERG changes were measured at approximately 2-week
intervals beginning 8 weeks after glaucoma surgery on AXK–anesthetized
rats.10
After at least 16 hours’ dark-adaptation, eyes
were dilated with a topical application of 1% tropicamide and 2.5%
phenylephrine. Custom-made contact lenses with a gold-wire ring
electrode on the concave surface and coated with 2.5% hydroxy propyl
methyl cellulose were applied to both eyes. Stimuli consisted of
10-µsec stroboscopic flashes of unattenuated white light (two, 1
minute apart) generated by a Grass PS-22 stimulus generator
(Grass Instruments, Quincy, MA; irradiance = 236 lux/s).
Data from both eyes were accumulated simultaneously and analyzed using
the LKC Technologies (Gaithersburg, MD) electrodiagnostic
recording instrument (model UTAS-2000) and software (LKC Technologies
Advanced Analysis). Differences between the G and contralateral N eyes
of each rat were calculated for the primary response parameters (a- and
b-wave amplitudes in negative microvolt and positive microvolt units,
respectively) and were analyzed by ANOVA and by paired
t-test.
RGC Labeling and Counting
RGCs were retrogradely labeled by injection of 1 µl volumes of
the amidine dye Fluorogold (Fluorochrome, Denver, CO)
fluorescent tracer (5% in H2O) into the superior
colliculus at 2 locations on each side using a Hamilton (Reno,
NV) syringe with a 33-gauge needle. Injections were performed by
placing the head of AXK–anesthetized rats on a stereotaxic apparatus
using coordinates from the rat brain atlas, essentially as previously
described.11
Rats were AXK–anesthetized 5 days after the
Fluorogold injections, perfused transcardially with 4%
paraformaldehyde in phosphate-buffered saline (PBS), and the eyes
enucleated. Eyecups were made by cutting off the anterior segment at
the level of the limbus, and the eyecups were immersion-fixed for 1
hour in 4% paraformaldehyde in PBS. Cuts were made through the sclera
to form a Maltese cross pattern, and the retinas detached from the
eyecup at the optic nerve head and fixed overnight in 1%
paraformaldehyde in PBS. Both retinas from one rat were flatmounted,
vitreous side up, on a glass slide, air-dried, and cover-slipped with
Advantage mounting medium (Axell). The retinas were visualized under
epifluorescence microscopy (Zeiss Axiomat with Omega Optical XF05
filter set) and scanned for the areas in which RGCs were absent
(patches). Also, in 8 of the rats 4 adjacent micrographs were taken in
the peripheral region of each quadrant of the G and N retinas (superior
nasal and temporal, inferior nasal and temporal) along the centerline
of each quadrant from eccentricity 2- to 4-mm distant from the center
of the optic nerve head using a 16x objective. Microscope fields
(400 x 300 µm) were selected to avoid obvious patches in which
RGCs were absent by moving the field laterally from the midline of the
quadrant at the same eccentricity. Some fields were photographed with
both epifluorescence and interference contrast (Nomarski) optics. The
RGCs in 16 fields of each retina were counted using a computer-based
image analysis system (Image-1; NIH) and totaled 2500 to 3000 RGCs in
G, N, or control (no surgery) retinas. RGC counts for each quadrant of
G retinas were calculated as percent of the counts ± SEM in the
corresponding quadrant of the contralateral N retina.
Significance between the mean cell counts in corresponding quadrants of
G and N retinas was determined by Student’s t-test.
N-Methyl-D-Aspartate Injections
Six rats were injected in one eye with 5 µl of sterile (0.22
µl filter, Millipore Corp., Bedford, MA)
N-methyl-D-aspartate solution (NMDA;
10 mM in PBS) via a 33-gauge microsyringe needle into the center of the
vitreous.12
Contralateral control eyes received a 5 µl
injection of sterile PBS. After 10 days the RGCs were retrogradely
labeled with Fluorogold, and the retinas prepared as above and
statistically analyzed as above.
Determination of Mitochondrial Membrane Potential and Nuclear DNA
Staining
Fifteen weeks after surgery the glaucomatous and contralateral N
eyes of 4 rats anesthetized with AXK were injected with the dye
CMTMR (MitoTracker orange; Molecular Probes, Eugene, OR), 5
µl of a 125-µM solution in aqueous 20% dimethyl
sulfoxide.13
After 30 minutes, the rats were perfused with
4% paraformaldehyde in PBS. Retinas were isolated as described above,
immersed for 2 hours in the nucleic acid–staining dye YOYO-1
(Molecular Probes), 3 µM in PBS, and then washed in PBS.
Flatmounts of the retinas were examined for fluorescence of CMTMR and
YOYO-1 by dual-channel confocal fluorescence microscopy. A Leica TCS-4D
confocal scanning microscope coupled to an argon-krypton laser
(Omnichrome,Wessling, Germany) was used to resolve 3000 to
4000 individual mitochondria labeled with CMTMR in the RGC layer of
each retina. A pinhole setting of 50 was used with an
excitation wavelength of 488 nm and a long-pass emission filter of 590
nm. Images were scanned using an oil immersion, 40x, 1.0 NA objective
at 512 x 512 x 8 bits per pixel resolution, background
offset at -1, and averaged 32 times in line-average scan mode. The
images were saved in tagged image file format (TIFF) and transferred to
a personal computer–run Metamorph software program (Universal Imaging)
to threshold individual mitochondrial outlines and then to measure the
mean intensity within each mitochondrion. The value for each
mitochondrion was normalized against mean intensity for the immediately
adjacent cytoplasm, and the values were presented as frequency
distributions. In an additional 2 rats, the retinas were isolated
without CMTMR injection as above and labeled with YOYO-1 alone.
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Results |
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100%
increase over the contralateral eye) for > 12 weeks with a high
degree of group consistency (Fig. 1A
). There was however also a much smaller but statistically significant
increase in IOP in the sham-operated control eyes relative to the
baseline over the first 8 weeks. When 5-FU treatment was omitted, the
IOP of the vein-occluded eyes returned to the same level as that in the
contralateral N eyes by 15 days post surgery in the majority of rats
(Fig. 1B) .
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Figures 3 and 4 show two representative fields from glaucomatous retinas, each taken with both fluorescence and Nomarski optics, as can be seen by coincidence of the retinal blood vessel pattern in each pair. The images show, respectively, 2 small patches and the edge of a larger patch in which RGCs are not detectable. The corresponding Nomarski images show that the patches are not holes or tears resulting from damage during preparation of the flatmounts. Occasionally, no fluorescent RGC are visible in a field because patches can be larger than the field at this magnification, as shown in the low-magnification micrograph taken with a 4x objective (Fig. 5) . Scanning of six glaucomatous rat retinas with patches gave an average of 5 to 6 such patches per retina with a size greater than 100 µm in the smallest dimension. Occasionally, areas without RGCs were evident in contralateral control retinas, but they appear to be mostly artifact caused by damage during preparation of flatmounts, because they occur near tears or the cuts made in the retina.
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The comparison of glaucoma- and NMDA-mediated loss of RGCs relative to the respective contralateral N control eye is shown in Figure 6 . This dose of intravitreous NMDA caused a 60% or greater loss of RGCs in all quadrants (P < 0.001), whereas in the glaucoma retinas only one quadrant (inferior temporal) showed a small but statistically significant loss of RGCs (P < 0.05).
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M) was also determined in the RGC layer of
four of the rats using the fluorescence intensity of CMTMR accumulated
by mitochondria of cells in the RGC layer as a relative marker of
membrane potential (Fig. 8)
.13
14
The retinas subjected to high IOP for 15 weeks
showed a lower mean level of mitochondrial CMTMR fluorescence in
regions surrounding the patches (82.5% ± 7.3%, P <
0.05) relative to mitochondria in randomly chosen areas of the RGC
layer at the same approximate eccentricity in the contralateral N eyes.
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Discussion |
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75% of the
surgeries as shown in Figure 1B , possibly because of restoration of
venous patency by growth of new vessels. This can be avoided by careful
surgical technique and, particularly, by subconjunctival 5-FU
injections. A few animals develop complications (lens or
cornea opacities), but survival to 15 weeks with elevated
IOP and otherwise apparently normal eyes is achieved in 80% of
surgeries that are followed by 5-FU treatment. The small elevation of
IOP that occurs in the contralateral N eyes may be a centrally mediated
response to the rise of IOP in the G eye, or may be a result of the
sham surgery plus 5-FU treatments. The ERG response measurements
suggest a decline in the amplitude of both a- and b-waves beginning
after approximately 3 months and, thus, becoming a significant feature
in this glaucoma model only after a prolonged time of elevated
IOP (Fig. 2)
. These results are similar to reports on ERG findings in
subjects with advanced open-angle glaucoma.15
16
However,
as in human glaucoma, more detailed analysis of ERG parameters at lower
light intensities, such as oscillatory potentials or pattern ERG, may
indicate glaucomatous retinal pathology at earlier times in this rat
glaucoma model.
The RGC loss that has occurred after 12 weeks of elevated IOP in this
model appears to be primarily focal. Additionally, the RGCs in areas
bordering a patch of missing cells showed a somewhat more disordered
spatial distribution when compared visually with the more regular
columnar arrangement of RGCs seen in N or control retinas (see Fig. 4
).
All the glaucomatous retinas showed obvious patches of missing RGCs,
but the number of such patches in individual G retinas was variable,
ranging from 3 to 12, and occurred in all quadrants of the retina.
Thus, the counting of the number of such patches is too subjective and
variable to be a reliable quantitative measure of RGC loss after 3 to 4
months of elevated IOP in this glaucoma model. Even if we could
determine the aggregate number of RGCs missing in the focal areas this
would likely be too small a fraction of the total RGCs to be a useful
quantitative measure. Most of the patches found were smaller than the
field size (0.12 mm2), and even if the maximum
number of patches observed were all this size, the number of missing
RGCs (4000) represents less than 4% of the total RGCs in a rat
retina.
The formation of a patch is most probably caused by the dead cells having been removed by phagocytic microglia before the time of Fluorogold labeling. It is also possible that RGC cell bodies are still present in a patch but do not label with Fluorogold because of axon pathology. However, if a patch gradually enlarges over time, the adjacent cells at the periphery might be under stress or in the initial stages of the death process and might exhibit characteristics of apoptosis. In fact, cells with condensed nuclei that stain strongly with YOYO-1 were most often found in regions near patches (see Fig. 7 and below). We believe that the patches result from the death of RGCs in a pattern comparable to the loss in human glaucoma and that this focal loss of RGCs might be sufficient to result in field defects if this could be measured in the rat eye.
We also evaluated whether there was a more evenly distributed loss of
RGCs in areas of the retina outside the patches. Sampling of 3% of
the total RGCs in representative fields in the peripheral retina in all
quadrants but outside patchy areas showed no significant loss within
the limits of the sampling technique. The same procedure was able to
determine the more uniformly distributed loss of 60% of the RGCs
resulting from the intravitreal injection of NMDA.12
In a
recent report on a rat glaucoma model with 2-vein occlusion similar to
the model in this study, but with prelabeling of RGCs using Fast Blue
(another amidine dye), a uniformly distributed loss of 50% of the
RGCs was found in the peripheral retina after 10 weeks of elevated
IOP.7
The sampling method, the number of RGCs counted, and
the retinal area counted (3%–3.5% of RGCs) was comparable to those
used in the present study. As shown by the positive control NMDA
experiment (Fig. 5)
, this level of uniform RGC loss in the glaucoma
retinas would have been detected by the sampling method used in this
study, but was not found. Thus, the pattern of RGC loss seems to be
shifted toward a more uniform loss when RGCs are subjected to both
dye-labeling and high IOP together over a period compared with the more
focal damage found in the present experiments when the prolonged insult
is elevated ocular pressure alone. One possible explanation of the
discrepancy between the present findings and previously published
results is the difference in marking of the RGCs, either by
post-labeling (present results) or prelabeling, with amidine dyes, such
as Fluorogold and Fast Blue, which are known to be toxic to some
neurons in long-term experiments.17
In a recent article,
Neufeld et al.6
reported on a very similar glaucoma model
in male Wistar rats5
after 6 months of elevated IOP and
found a uniform loss of RGCs of 35% in the peripheral retina after
post-labeling with Fluorogold, a result also considerably less than the
50% loss after 3 months reported with prelabeling. In this case
15% of the total retinal area was sampled for RGC counts. These
findings taken together with the present results suggest that
prelabeling with amidine dyes that are potentially toxic to RGCs should
be avoided, that a uniform loss of RGCs becomes more apparent after 6
months of elevated IOP, and that at least 15% of the retinal area
needs to be counted to quantitate RGC loss. Our findings after 3 to 4
months of glaucoma are in general agreement with the results of
Morrison and coworkers4
on the patterns of axon loss in
the optic nerves of rats with chronically elevated IOP induced by the
saline injection method.
The mode of RGC death in glaucoma is thought to be mainly via an
apoptotic mechanism.18
19
20
If RGC death is an ongoing
process in the glaucomatous rat retina there should have been some
cells in various stages of apoptosis at the time the retinas were
isolated. YOYO-1–stained condensed nuclei, representing late stages of
cell death by apoptosis, were consistently present in all the
glaucomatous retinas. However, a relatively early stage in cellular
stress that can proceed to apoptosis is a decrease in mitochondrial
membrane potential occurring before changes in nuclear DNA. These
markers, in mitochondria and in nuclei, can be assessed in the same
retina by dual-channel fluorescence confocal microscopy after labeling
with both the CMTMR and a DNA-binding dye such as YOYO-1. The intensity
of the CMTMR fluorescent label in mitochondria, a relative measure of
mitochondrial membrane potential, showed a significant downward shift
in distribution in the RGC layer (Fig. 8)
, indicating a larger number
of cells with reduced mitochondrial potential in glaucomatous retinas
relative to N retinas. However, because 45% of cells in the RGC
layer are displaced amacrine cells,21
which will also have
their mitochondria labeled with CMTMR, the loss of mitochondrial
potential specifically in RGCs could be larger than the overall 17.5%
mean decrease actually measured, or the proportion of RGC cells
affected could be greater. These findings indicate that a significant
number of functional RGCs may exhibit markers of cellular stress when
subjected to a prolonged period of elevated pressure and that it is
most likely from this population that individual cells proceed over
time to apoptotic cell death.
In conclusion, we found that the 3-vein occlusion model for inducing glaucoma in the rat eye provides a consistent long-term pressure elevation. After 12 to 15 weeks of high IOP there is a variable focal loss of RGCs, and some of the remaining cells show changes characteristic of stress and apoptosis. By 16 weeks of high IOP there is a significant decline in amplitude of the scotopic ERG a- and b-waves. These changes seem consistent with retinal damage that causes field defects in human glaucoma, and, thus, this rat model appears to mimic some features of primary open-angle glaucoma.
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Footnotes |
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Submitted for publication August 31, 1999; revised December 28, 1999, and March 30, 2000; accepted April 19, 2000.
Commercial relationships policy: N.
Corresponding author: Thom W. Mittag, Department of Ophthalmology, Box 1183, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029-6574. thomas.mittag{at}mssm.edu
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R. Naskar, M. Wissing, and S. Thanos Detection of Early Neuron Degeneration and Accompanying Microglial Responses in the Retina of a Rat Model of Glaucoma Invest. Ophthalmol. Vis. Sci., September 1, 2002; 43(9): 2962 - 2968. [Abstract] [Full Text] [PDF]
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B. C. Chauhan, J. Pan, M. L. Archibald, T. L. LeVatte, M. E. M. Kelly, and F. Tremblay Effect of Intraocular Pressure on Optic Disc Topography, Electroretinography, and Axonal Loss in a Chronic Pressure-Induced Rat Model of Optic Nerve Damage Invest. Ophthalmol. Vis. Sci., September 1, 2002; 43(9): 2969 - 2976. [Abstract] [Full Text] [PDF]
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J. Benozzi, L. P. Nahum, J. L. Campanelli, and R. E. Rosenstein Effect of Hyaluronic Acid on Intraocular Pressure in Rats Invest. Ophthalmol. Vis. Sci., July 1, 2002; 43(7): 2196 - 2200. [Abstract] [Full Text] [PDF]
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S. Husain, I. Kaddour-Djebbar, and A. A. Abdel-Latif Alterations in Arachidonic Acid Release and Phospholipase C-{beta}1 Expression in Glaucomatous Human Ciliary Muscle Cells Invest. Ophthalmol. Vis. Sci., April 1, 2002; 43(4): 1127 - 1134. [Abstract] [Full Text] [PDF]
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H. Levkovitch-Verbin, H. A. Quigley, K. R. G. Martin, D. Valenta, L. A. Baumrind, and M. E. Pease Translimbal Laser Photocoagulation to the Trabecular Meshwork as a Model of Glaucoma in Rats Invest. Ophthalmol. Vis. Sci., February 1, 2002; 43(2): 402 - 410. [Abstract] [Full Text] [PDF]
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E. WoldeMussie, G. Ruiz, M. Wijono, and L. A. Wheeler Neuroprotection of Retinal Ganglion Cells by Brimonidine in Rats with Laser-Induced Chronic Ocular Hypertension Invest. Ophthalmol. Vis. Sci., November 1, 2001; 42(12): 2849 - 2855. [Abstract] [Full Text] [PDF]
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A. U. Bayer, T. Neuhardt, A. C. May, P. Martus, K.-P. Maag, S. Brodie, E. Lütjen–Drecoll, S. M. Podos, and T. Mittag Retinal Morphology and ERG Response in the DBA/2NNia Mouse Model of Angle-Closure Glaucoma Invest. Ophthalmol. Vis. Sci., May 1, 2001; 42(6): 1258 - 1265. [Abstract] [Full Text]
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M) in mitochondria of the
RGC layer in the retinas from two rats (1 and 2) with glaucomatous (G)
left eyes and their contralateral control (N) right eyes. The mean
fluorescence intensity ± SD is given for the frequency
distribution determined for each eye. Representative of similar
distribution experiments done in 4 rats.